The virus causing the acquired immunodeficiency syndrome (AIDS) is generally known as the human immunodeficiency virus (HIV). The spread of HIV has caused and continues to cause serious health problems throughout the world. A number of HIV inhibitory drugs have been developed that currently are used to combat the virus. These drugs have proven out to be effective in suppressing the virus, in particular when used in combination therapy. However no therapy is capable of completely eliminating the virus from the body.
Several classes of HIV inhibitors at present are available and new ones are being explored. One such class is that of that of the non-nucleoside reverse transcriptase inhibitors (NNRTIs). This class comprises a number of drugs that are used in anti-HIV therapy while other NNRTIs are in various stages of development. One of these is the compound 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, also known as TMC278. This compound, its properties as well as a number of synthetic approaches for its preparation have been described in WO-03/16306. TMC278, which currently is in clinical development, not only shows pronounced activity against wild type virus, but also against many mutated variants.
Consequently there is a need for producing larger quantities of this active ingredient based on processes that provide the product in high yield and with a high degree of purity. A synthesis strategy that has been developed to prepare this compound involves coupling (E)-4-amino-3,5-dimethylcinnamonitrile (B) with anilinopyrimidine (C) to obtain TMC278 as outlined in the following reaction scheme, wherein the compound TMC278 is represented by formula (A).

The preparation of intermediate (B) has been described in WO-04/016581 as comprising coupling 4-iodo-2,6-dimethylaniline (D) (X═I) with acrylonitrile in the presence of palladium on charcoal, sodium acetate as a base and dimethylacetamide as a solvent.

The preparation of intermediate (C) on the other hand has been described in WO-03/16306 as comprising a halogenation reaction of 4-oxo-1,6-dihydro-pyrimidine (I), in particular with POCl3.

Compound (I), which sometimes is represented by its tautomeric form (I′):
can be prepared following the procedure described in Synthetic Communications, 27(11), 1943-1949 (1997):

The reaction of (E) with (F) results in the liberation of methyl mercaptane, a toxic and extremely odorous compound, which can be smelled at concentrations as low as 2 ppb. Complete removal of this mercaptane therefore is a requirement, posing a very difficult purification challenge. This makes this process impractical for large-scale production.
WO-00/27825 discloses at p. 14 the synthesis of structural analogs of compound (I) bearing a Y substituent in 5-position and a Q substituent in 6-position of the pyrimidine moiety. The group Y in these structural analogs cannot be hydrogen and in particular is halogen and is never a carboxyl ester group as required in the process of the present invention. Moreover the synthesis disclosed in this reference lacks a decarboxylation step, which is essential in the process of the present invention.
Although the above mentioned prior art process via intermediates (E) and (F) may be useful for preparing small quantities of the desired product of formula (I), there is a need for a process that can be scaled up for the production of multi-kilogram and larger quantities, that is reproducible, is economical and through which the end product is obtained in high yield and with a high degree of purity. Providing such a process is an object of the present invention.